The olfactory system exhibits a remarkable regenerative capacity, both in its ongoing replacement of olfactor neurons and its ability for repair in response to chemical or surgical trauma. The processes of neurogenesis and synaptogenesis are nutritionally demanding, and occur only during development in other central nervous system (CNS) tissues. While much is known about the adverse impact of inadequate nutritional status on prenatal growth and development, little is known about nutritional influences on the ongoing regenerative processes within the olfactory system. Recently, food restriction was shown to impair the regeneration of olfactory epithelium following chemically-induced degeneration (Schwob et all, 1994). The mechanisms for this type of nutritional modulation of olfactory system regeneration have not been studied directly. Two nutritionally modulated factors, insulin and insulin-like growth factor I (IGF-I) influence growth, differentiation and survival of a variety of neuronal systems. Interestingly, these neurotrophic factors are also found in dramatically higher levels in the olfactory bulb than most other brain areas. These observations suggest the integrity of the olfactory system may be more sensitive to nutritional modulation than most CNS tissues. However, little is known about the functions of insulin and IGF-I in t he olfactory system, or their synthesis or distribution within the epithelium, where the initial phases of regeneration occur. This proposal postulates that nutritional status influences the ability of the olfactory system to carry out its regenerative processes, both ongoing and in response to trauma, and that insulin and IGF-I contribute to this effect. The proposed project will use a multidisciplinary approach to examine the effect of altered nutritional status ont he structural and functional integrity of the olfactory system, both under normal condiitons and following surgical trauma to trigger rapid olfactory neuron degeneration and regeneration. This goal will be pursued through following the Specific Aims: (1) Determine whether cells within olfactory epithelium express insulin or IGF-I mRNAs or their receptor mRNAs or proteins: (2) investigate the effects of protein-restriction (PR), and streptozotocin-induced diabetes (StD) on olfactory system structure and function; (3) determine whether levels of insulin or IGF-I mRNA, or their receptor proteins or mRNAs in the olfactory bulb and epithelium change in response to olfactory nerve section; (4) Determine whether altered nutritional status (PR and StD) influences repair of the olfactory system in response to surgical trauma. The results of these studies will establish the olfactory system as a model to investigate nutritional modulation of neuronal regeneration and function and will provide new insight into the roles of insulin and IGF-I in the olfactory system. In addition, results may contribute to a better understanding of the neuropathologic effects of impaired nutritional status as seen in diabetes and malnutrition.